Respiratory muscle fatigue has been proven to contribute to the pathogenesis of hypercapnic respiratory failure in a variety of conditions. Since the original work that we pioneered on the subject, we have been working with several animal and human models in order to elucidate the underlying mechanisms of respiratory muscle fatigue. Our experience has convinced us that one of the most potent factors that we have tested which readily produces muscle fatigue is the inadequate blood flow. Thus, we propose in this grant to further investigate the role that blood flow plays in the development of respiratory muscle fatigue. The aim of the First Project is to better characterize the diaphragmatic arterial flow relations. We will first determine the autoregulatory reserves of the diaphragm as well as the "critical pressure" below which diaphragmatic function becomes dependent on blood pressure. We hypothesize that this "critical pressure" will be higher the greater the flow demands. We will then determine the dynamic pressure flow relations of the phrenic artery. Our general hypothesis is that the arterial pressure at zero flow (Pz) is much above venous pressure and therefore flow to the diaphragm can be affected by changes in Pz, the conductance (Cd) (slope of the pressure-flow relation), or both. We also hypothesize that the Pz will decrease and Cd increase with increased diaphragmatic flow demands produced by increasing diaphragmatic contraction rate. We hypothesize that at high rates of contraction Pz rises and limits further increases in flow. In these experiments we will also determine the effects of increases in venous pressure on Pz. Finally, we will determine the role of alpha adrenergic and smooth muscle tone on Pz by giving specific pharmacological blockers. The Second Project is designed to investigate the role and the mechanisms of respiratory muscle fatigue in the development of ventilatory failure in a state of decreased blood pressure and cardiac output. The hypothesis is that in this model, while the work of breathing increases, respiratory muscle blood flow decreases (secondary to a decrease in arterial pressure), and oxygen extraction is impaired (secondary to endotoxic tissue dysfunction), all of which lead to an imbalance of energy supply-demand and thus to fatigue. Fatigue in these projects will be assessed by measuring the force at a given EMG activation as well as by evaluating the changes of muscle metabolites, including ATP, Pi, CP, G-6-P, pyruvate, lactate and glycogen.